Hypoparathyroidism is a rare disease that results from a deficiency or inability to make sufficient amounts of parathyroid hormone (PTH). Untreated or inadequately treated hypoparathyroidism leads to clinically significant metabolic issues including hypocalcemia, which can be life-threatening. Current management of the disease for the majority of patients consists of supplemental doses of calcium and active vitamin D to manage hypocalcemia. While this approach is intended to maintain serum calcium, it does not correct the underlying PTH deficiency. Therefore, the physiological aspects of hypoparathyroidism, including lack of endogenous 1,25-dihydroxyvitamin D production, hypercalciuria, hyperphosphatemia, and metabolic bone abnormalities can still occur. Moreover, supplementation is associated with several challenges, namely, long-term complications from the use of these vitamins in the absence of endogenous PTH hormone, which contributes to renal function deterioration, kidney stones, and soft tissue calcifications. Clinical trials have demonstrated that PTH(1-34) must be dosed continuously via a pump in humans in order to mimic physiological levels of PTH to restore normal levels of calcium, phosphorus and markers of bone turnover. However, a pump- mediated, continuous infusion of PTH would be costly and inconvenient for patients. Extend Biosciences is proposing to develop a long-acting version of PTH(1-34) that could be dosed far less frequently and still achieve a prolonged pharmacokinetic profile that approximates endogenous levels. Our proprietary carrier molecule lengthens circulating half-life and improves subcutaneous bioavailability, but is small enough so as not to interfere with the activity of a peptide to which it is conjugated. Preliminary results show that carrier- conjugated PTH has the same EC50 for receptor activation as unconjugated PTH. Additionally, when the carrier is conjugated to PTH, it significantly extends the half-life in rodents. The studies proposed in this Phase I application will analyze the pharmacological properties of the long-acting PTH(1-34) and investigate efficacy in an animal model of hypoparathyrodism by looking at the ability of the long-acting PTH to reverse several markers of disease. This will show the feasibility and in vivo functionality of long-acting PTH(1-34). SBIR Phase II funding will focus on IND-enabling studies including GLP production, dose range finding and toxicology/immunogenicity studies. Once fully developed, this long-acting PTH(1-34) derivative would provide a patient-friendly therapy for hypoparathyroidism that will significantly improve the prognosis and quality of life in patients with this disease.